Prostaglandin D2 (PGD2) has long been associated with inflammatory and atopic conditions, specifically allergic diseases such as asthma, rhinitis, conjunctivitis and atopic dermatitis (Lewis et al. (1982) J. Immunol. 129, 1627). PGD2 belongs to a class of compounds derived from the 20-carbon fatty acid skeleton of arachidonic acid. In response to an antigen challenge, PGD2 is released in large amounts into the airway as well as to the skin during an acute allergic response. The DP receptor, which is a member of the G-protein coupled receptor (GPCR) subfamily, has long been thought to be the only receptor of PGD2. DP's role in allergic asthma has been demonstrated with DP deficient mice (Matsuoka et al. (2000) Science 287, 2013-2017). However, despite intense interest in the role of PGD2 in the inflammatory response, a direct link between DP receptor activation and PGD2-stimulated eosinophil migration has not been established (Woodward et al. (1990) Invest. Ophthalomol. Vis. Sci. 31, 138-146; Woodward et al. (1993) Eur. J. Pharmacol. 230, 327-333).
More recently, another G-protein coupled receptor, referred to as “Chemoattractant Receptor-Homologous molecule expressed on T-Helper 2 cells” (CRTH2) (Nagata et al. (1999) J. Immunol. 162, 1278-1286, Hirai et al. (2001) J Exp. Med. 193, 255-261) has been identified as a receptor for PGD2 and this discovery has begun to shed light on the mechanism of action of PGD2. CRTH2, which is also referred to as DP2, GPR44 or DLIR, shows little structural similarity with the DP receptor and other prostanoid receptors. However, CRTH2 possesses similar affinity for PGD2. Among peripheral blood T lymphocytes, human CRTH2 is selectively expressed on Th2 cells and is highly expressed on cell types associated with allergic inflammation such as eosinophils, basophiles and Th2 cells. In addition, CRTH2 mediates PGD2 dependent cell migration of blood eosinophils and basophiles. Furthermore, increased numbers of circulating T cells expressing CRTH2 have been correlated with the severity of atopic dermatitis (Cosmi et al. (2000) Eur. J. Immunol. 30, 2972-2979). The interaction of CRTH2 with PGD2 plays a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. Compounds that inhibit the binding of CRTH2 and PGD2 should therefore be useful for the treatment of allergic diseases.
Allergic disease, like asthma, and inflammatory dermatoses represent a major class of complex, and typically chronic, inflammatory diseases that currently affect about 10% of the population and that number appears to be increasing (Bush, R. K., Georgitis J. W., Handbook of asthma and rhinitis. 1st ed. (1997), Abingdon: Blackwell Science. 270). Atopic dermatitis is a chronic skin disease, wherein the skin becomes extremely itchy. It accounts for 10 to 20 percent of all visits to dermatologists. The increasing incidence of allergic diseases and inflammatory dermatoses worldwide underscores the need for new therapies to effectively treat or prevent these diseases. Currently, numerous classes of pharmaceutical agents are widely used to treat these diseases, for example, antihistamines, decongestants, anticholinergics, methylxanthines, cromolyns, corticosteroids, and leukotriene modulators. However, the usefulness of these agents is often limited by side effects and low efficacy.
It has been reported recently that 3-sulphur-substituted indole derivatives (A) exhibit CRTH2 activity (WO 04/106302, AstraZeneca AB) and are potentially useful for the treatment of various respiratory diseases.
WO 04/096777 (Bayer Healthcare AG) relates to pyrimidine derivatives, which are useful for the treatment of diseases mediated by CRTH2.
WO 04/035543 and WO 05/102338 (Warner-Lambert Company LLC) disclose tetrahydrochinoline derivatives as CRTH2 antagonists (C), which are also described to be effective in the treatment of neuropathic pain.
Specific tetrahydrochinoline derivatives as CRTH2 modulators are also provided by WO 04/032848 (Millennium Pharmaceutical Inc.) and WO 05/007094 (Tularik Inc.). These tetrahydrochinoline derivatives are said to be useful for treating disorders associated with allergic inflammation processes.
Patent applications WO2005115382, WO2007062678, and WO2007062773 also provides phenoxyacetic acid derivatives as ligands of CRTH2 receptors.
The invention further provides a pharmaceutical composition comprising a compound of Formula (I), together with a pharmaceutically acceptable excipient or carrier.
The invention further relates to a kit or a set comprising at least one compound of Formula (I), preferably in combination with immunomodulating agents. Alternatively, the kit consists of separate packs of:
(a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and
(b) an effective amount of a further medicament active ingredient.
The invention further relates to the use of compounds of Formula (I) for the preparation of a medicament for the treatment and/or prevention of diseases selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases or disorders associated with CRTH2 activity. Specifically the present invention is related to the use of compounds of Formula (I) for the modulation, notably the inhibition of CRTH2 activity.
The invention further relates to a method for treating and/or preventing a patient suffering from a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases and disorders associated with CTRH2 activity, by administering a compound according to Formula (I).
The invention further relates to the use of compounds of Formula I for the preparation of a pharmaceutical composition.
The invention finally relates to novel compounds of Formula I as well as to methods to synthesize these molecules.
In another embodiment, the present invention provides compounds of Formula (IA)
As well as its ester derivatives, its geometrical isomers, its optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.WhereinR1* is H, Hal, A, CN, NO2, OA, CF3, OCF3,Q* is Ar*, Het*,n is 1, 2, 3, or 4,Z* is phenyl or pyridinyl,A is branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non-adjacent CH2— groups may be replaced by O, NR3 or S and/or by CH═CH— or —C≡C— groups, or denotes cycloalkyl or cycloalkylalkylen having 3 to 7 ring C atoms,Hal is F, Cl, Br or I,Ar* denotes a monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, —CH2OR3, OR3, CF3, OCF3, N(R3)2, NO2, CN, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, SO2A, Het, or by SO2T,T denotes —(CH2)p—Ar′ or —(CH2)p-Het′,p is 0, 1, 2, 3 or 4,Ar′ denotes a monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, —CH2OA, —CH2OR3, —OR3, —CF3, —OCF3,Het′ denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring, having 1 to 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, OR3, CF3, OCF3,Het* denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring, having 1 to 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, OR3, CF3, OCF3, N(R3)2, NO2, CN, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, SO2A, SO2T,R3 is H or A,
In a preferred embodiment, the invention provides compounds of Formula (Ia):
wherein R1* and Q* are as above defined,as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
In a preferred embodiment, the invention provides compounds of Formula (Ib):
Wherein R1 is as above definedR4 is N(R3)2, A or T,R5 is H, Hal, A, CF3, SO2A, SO2N(R3)2, or SO2T,with A, T and R3 being as above defined,as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
In another preferred embodiment, the invention provides compounds of Formula (Ic):
wherein R1* and R5 are as above defined.
In another preferred embodiment, the invention provides compounds of Formula (Id):
wherein R1* is as defined above, R5 is Hal, and R6 is A, CH2OA,as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
In another preferred embodiment, the invention provides compounds of Formula (Ie):
wherein Q* and n are as above defined,as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
In another preferred embodiment, the invention provides compounds of Formula (If)
wherein Q*, R1* and n are as above defined,as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and its racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
In another preferred embodiment, the invention provides compounds of Formula (Z):
Wherein R1, Rx, Ry, m and n are as defined under Formula (I),L denotes SO2, SO, or O, preferably SO2;W denotes C or N, preferably C,U denotes H, Hal, RZ,V denotes H, Ar′, RZ, CORZ, CONHRZ, and if linked to J also —CO—, —CONRZ, or an arylen,J denotes RZ, NHRZ, N(RZ)2, (CH2)sAr′, whereby s is 0 or 1; and if linked to V also —NRZ, or (CH2)sAr″; whereby an arylen denotes a di-, tri-, or tetravalent Ar′ group, or when L is O, J also denotes H,and wherein J and V may be linked to each other to form a ring.RZ denotes a linear or branched alkyl or alkenyl having 1 to 6 carbon atoms, optionally substituted by OH, or OCH3;Ar″ denotes an arylen which may be further substituted by 1 or 2 groups selected from OR3, Hal, CF3 wherein R3 is as above defined.as well as their ester derivatives, their geometrical isomers, their optically active enantiomers, diastereoisomers and their racemates forms, and tautomers, or a pharmaceutically acceptable derivative thereof.
Ar preferably denotes a monocyclic or bicyclic aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted, monosubstituted or disubstituted by Hal, A, CH2OA, OR3, CF3, OCF3, N(R3)2, NO2, CN, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, SO2A, SO2T, wherein T is as defined above.
More preferably, Ar is selected from the following groups:
wherein Ra denotes H, alkyl having 1 to 6 carbon atoms, Hal, CF3, —OR3, and Rb denotes H, Hal, CF3, —SO2N(R3)2, —SO2R3, CH2OR3, SO2T.
Het preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring, having 1 to 3 N, O and/or S atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, OR3, CF3, OCF3, N(R3)2, NO2, CN, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, SO2A, SO2T, wherein T is as above defined.
More preferably, Het denotes a monocyclic, unsaturated or aromatic heterocyclic ring, having 1 to 3 N, and/or S atoms, which may be unsubstituted, monosubstituted or disubstituted by Hal, A, CH2OA, OR3, CF3, OCF3, N(R3)2, NO2, CN, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, SO2A, SO2T, wherein T is as above defined.
More preferably, Het denotes one of the following groups:
wherein Ra, Rb independently from one another denotes an alkyl group having 1 to 6 carbon atoms, H, Hal, CN, CF3, —OMe, —OEt, (CH2)qCH3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOH, —SO2(CH2)qOH, —SO2NH(CH2)qO(CH2)qCH3, —SO2(CH2)qO(CH2)qCH3, or SO2T wherein q denotes 0, 1, 2, 3 or 4;Rc denotes H, Me, or Et,Rd denotes H or a branched or linear alkyl having 1 to 6 carbon atoms,and r is 0, 1, 2 or 3.
Q is preferably Ar, more preferably a phenyl group.
Most preferably, when Q is Het, Het denotes one of the following groups:

In another preferred embodiment, the invention provides compounds of Formula (I) wherein Q is selected from the following groups:
Wherein Ra, Rb independently from one another denotes H, Hal, CN, OH, CF3, —OMe, —OEt, (CH2)qCH3, —(CH2)q(CH)(CH3)2, —SO2NH(CH2)qCH3, —SO2NH(CH2)qC(CH3)3, —SO2N(C2H5)2, —SO2(CH2)qCH3, —SO2(CH)(CH3)2, SO2(CH2)qCH(CH3)2, —SO2NH(CH2)qOH, —SO2(CH2)qOH, —SO2NH(CH2)qO(CH2)qCH3, —SO2(CH2)qO(CH2)qCH3, N(CH3)—SO2—(CH2)qCH3, —Ar′, —(CH2)Ar′, or SO2T, wherein q denotes 0, 1, 2, 3 or 4,and wherein Rx denotes H, Me, Et.
Most preferably, when R1 is Het, R1 denotes one of the following groups:

Otherwise R1 preferably denotes H, Cl, F, CN, —CH3, —CF3, or a phenyl group optionally substituted by an alkyl having 1 to 6 carbon atoms, and most preferably H, Cl, or a phenyl group optionally substituted by an alkyl having 1 to 6 carbon atoms.
A preferably denotes a branched or linear alkyl having 1 to 6 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non-adjacent CH2— groups may be replaced by O, NR3 or S.
Het′ preferably denotes a monocyclic saturated, heterocyclic ring, having 1 to 3 N, and/or O atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, OR3, CF3, OCF3.
Most preferably, Het′ denotes one of the following groups:

Ar′ preferably denotes a phenyl group.
n is preferably 1 or 2
—OR3 preferably denotes one of the following groups: —OH, O(C1-C6)alkyl, most preferably, OH or OMe.
An “alkyl” or “alky group” denotes a linear or branched carbon chain having 1 to 6 carbon atoms. Preferably, an “alkyl” or an “alkyl group” denotes a linear or branched carbon chain having 1 to 4 carbon atoms.
The term “ester” or “ester derivatives” refers to compounds of Formula (I) wherein one or more carboxylic function is protected with an alkyl, Ar, Het or benzyl group, preferably with a tert-butyl group.
The term “arylen” refers to a divalent monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring, having 6 to 14 carbon atoms. “Arylen” preferably refers to a phenylene group optionally substituted with OR3, Hal, and/or CF3, wherein R3 is as above defined.
In a preferred embodiment, the invention also provides compounds of Formula (I′) or (IA′)
wherein D denotes an alkyl, a benzyl group, Ar or Het.
D preferably denotes an alkyl, preferably tert-butyl, or a benzyl group.
In another preferred embodiment, the invention provides compounds of Formula (IA) wherein R1* is as defined under (IA) and wherein Q* denotes a phenyl optionally substituted with Hal, —OMe, CN, CF3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOR3, —SO2(CH2)qOR3, —(CH2)qCH3, —(CH2)qOR3, wherein q and R3 are as above defined.
In another preferred embodiment, the invention provides compounds of Formula (IA) wherein R1* is as defined under Formula (IA) and wherein Q* denotes a phenyl optionally substituted with an alkyl having 1 to 6 carbon atoms.
In another preferred embodiment, the invention provides compounds of Formula (IA) wherein R1* is as defined under Formula (IA) and wherein Q* denotes a pyridinyl optionally substituted with Hal, —OMe, CN, CF3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOR3, —SO2(CH2)qOR3, —(CH2)qCH3, —(CH2)qOR3, wherein q and R3 are as above defined.
In another embodiment, the invention provides compounds of Formula (IA) wherein R1* is as defined under Formula (IA) and wherein Q* denotes a thienyl optionally substituted with Hal, —OMe, CN, CF3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOR3, —SO2(CH2)qOR3, —(CH2)qCH3, —(CH2)qOR3, wherein q and R3 are as above defined.
In another embodiment, the invention provides compounds of Formula (IA) wherein R1* is as defined under Formula (IA) and wherein Q* denotes an imidazol optionally substituted with Hal, —OMe, CN, CF3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOR3, —SO2(CH2)qOR3, —(CH2)qCH3, —(CH2)qOR3, wherein q and R3 are as above defined.
In another preferred embodiment, the invention provides compounds of Formula (IA) and related formulae wherein Q* is as defined above and wherein R1* is Hal, —(CH2)qCH3, CN, CF3, —O(CH2)qCH3, wherein q is 0, 1, 2, 3, or 4, preferably 0, 1 or 2.
In another preferred embodiment, the invention provides compounds of Formula (I) wherein Q denotes a phenyl or a pyridinyl optionally substituted with Hal, —OMe, —OH, —CN, —CF3, —SO2NH(CH2)qCH3, —SO2(CH2)qCH3, —SO2NH(CH2)qOR3, —SO2NR3(CH2)qOR3, —SO2(CH2)qOR3, —(CH2)qCH3, —(CH2)qOR3, —SO2(CH2)qC(CH3)2, SO2(CH2)qAr, SO2N(CH3)2, NR3CO(CH2)qCH3, wherein q and R3 are as defined under Formula (I).
The preferred compounds of the invention are selected from the following group:
Ex.Formula1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173
“Pharmaceutically acceptable cationic salts or complexes” is intended to define such salts as the alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium or magnesium), aluminium salts, ammonium salts and salts with organic amines such as with methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-Me-D-glucamine, N,N′-bis(phenylmethyl)-1,2-ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, piperidine, benzathine (N,N′-dibenzylethylenediamine), choline, ethylene-diamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, thromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), procaine as well as amines of formula —NR,R′,R″ wherein R, R′, R″ is independently hydrogen, alkyl or benzyl. Especially preferred salts are sodium and potassium salts.
“Pharmaceutically acceptable salts or complexes” refers to salts or complexes of the below-identified compounds of Formula I that retain the desired biological activity. Examples of such salts include, but are not restricted to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disul-fonic acid, and poly-galacturonic acid. Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt of the Formula —NR,R′,R″+Z−, wherein R, R′, R″ is independently hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
“Pharmaceutically active derivative” refers to any compound that, upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
The compounds of the present invention according to Formula (I) are useful in the treatment and/or prevention of diseases selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD) rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease.
In one aspect the compounds according to Formula (I) are suitable as modulators, notably as antagonists, of CRTH2. Therefore, the compounds of the present invention are also particularly useful for the treatment and/or prevention of disorders, which are mediated by CRTH2 activity. Said treatment involves the modulation of CRTH2, notably an inhibition of CRTH2 or an antagonizing effect of CRTH2 in mammals, and in particular in humans. The modulators of CRTH2 are selected from the group consisting of an antagonist, an inverse agonist, a partial agonist and an agonist of CRTH2.
In another embodiment, the modulators of CRTH2 are antagonists of CRTH2.
In one embodiment, the modulators of CRTH2 are inverse agonists of CRTH2.
In another embodiment, the modulators of CRTH2 are partial agonists of CRTH2.
In another embodiment, the modulators of CRTH2 are agonists of CRTH2.
The compounds according to Formula (I) are suitable for use as a medicament.
Compounds of Formula (I) include also their geometrical isomers, their optically active forms as enantiomers, diastereomers, its racemate forms and tautomers, as well as pharmaceutically acceptable salts thereof, wherein:
In a second aspect, the invention provides a pharmaceutical composition comprising a compound according to Formula (I), together with a pharmaceutically acceptable excipient or carrier.
In a third aspect, the invention provides the use of a compound according to formulae (I) for the preparation of a medicament for the treatment and/or prevention of a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis and other diseases with an inflammatory component such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases and disorders associated with CTRH2 activity.
In a fourth aspect, the invention provides a method for treating and/or preventing a patient suffering from a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases and disorders associated with CTRH2 activity, by administering a compound according to Formula (I).
The term “preventing”, as used herein, should be understood as partially or totally preventing, inhibiting, alleviating, or reversing one or more symptoms or cause(s) of allergic disease or inflammatory dermatitis.
In a fifth aspect, the invention provides the use of a compound of Formula (I) for the preparation of a pharmaceutical composition useful for a variety of therapies, including preventing and/or treating a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases and disorders associated with CTRH2 activity.
The invention provides further the use of a compound of Formula (I) for preventing and/or treating a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease and other diseases and disorders associated with CTRH2 activity.
The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The compounds according to Formula (I) of the present invention are typically administered in form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
The pharmaceutical compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the substituted methylene amide derivative according to the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as pepper-mint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As above mentioned, substituted methylene amide derivatives of Formula (I) in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
The above-described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 5 of Remington's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pa., which is incorporated herein be reference. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington's Pharmaceutical Sciences. 
The compounds according to formula (I) can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), μL (microliter), ACN (acetonitrile), BOC (tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl3 (deuterated chloroform), CD3OD (deuterated methanol), CH3CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d6 (deuterated dimethylsulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-spray ionization), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), K2CO3 (potassium carbonate), LC (Liquid Chromatography), MeOH (methanol), MgSO4 (magnesium sulfate), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), Mtr. (4-Methoxy-2,3,6-trimethylbenzensulfonyl), NaHCO3 (sodium bicarbonate), NaBH4 (sodium borohydride), NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), POA (phenoxyacetate), PyBOP® (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBAF (tetrabutylammonium fluoride), TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoro borate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).
“O-PG” denotes a protecting group, preferably for acyl groups, i.e an acyl-protecting group. O-PG denotes preferably an O-alkyl group like tert-butoxy, methoxyl, ethoxy or benzyloxy group.
The term “protecting group” is known in general terms and relates to groups which are suitable for protecting a functional group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. The nature and size of the protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms.
In general, compounds according to Formula (I) of this invention can be prepared from readily available starting materials. If such starting materials are not commercially available they can be prepared by standard synthetic techniques. The following general methods and procedures described hereinafter in the examples can be employed to prepare compounds of Formula (I).
Depending on the nature of R1, Rx, Ry, Q, m and n in formula (I), different synthetic strategies may be selected for the synthesis of compounds of Formula I. In the process illustrated in the following schemes R1, Rx, Ry, Q, X, m and n are as defined in the description.
Generally, compounds of Formula (I), wherein R1, Rx, Ry, Z, Q, m and n are defined as above, can be obtained in 2 steps as outlined in Scheme 1. The first step consists in coupling a compound of Formula (II), wherein R1, Rx, Ry, Z, Q, m and n are defined as above, X denotes Cl, Br, I, preferably Br or I, or trifluoromethanesulfonyl and wherein PG denotes a protecting group such as tert-butyl, with an alkyne of Formula (III), wherein Q is defined as above. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling. The reaction can optionally be performed with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II) or 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. Additionally, the reaction can optionally be performed in the presence of a suitable copper salt such as but not limited to copper (I) iodide, copper (I) bromide or copper (I) chloride. The reaction can be performed in the presence or absence of bases such as TEA, DIEA, NMM, piperidine, Cs2CO3, sodium phosphate, in the presence or absence of a suitable solvent such as THF, ACN, DMF, acetone at a temperature between about 20° C. to about 100° C., preferably at about 70° C., for a few hours, e.g. one hour to 24 h. For a list of conditions described for the coupling of an aryl alkyne with an aryl or heteroaryl triflate or halide, see also Rafael Chinchilla and Carmen Najera, Chem. Rev. 2007, 107, 874-892.
Conversion of compounds of Formula (IV) to give compounds of Formula (I) can be achieved using conditions and methods well known to those skilled in the art for the conversion of an ester to a carboxylic acid, such as but not limited to treatment with a base or an appropriate acid, such as trifluoroacetic acid or hydrochloric acid, in the presence of a suitable solvent such as DCM, dioxane, THF at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.

Compounds of Formula (II), wherein R1, Rx, Ry, Z, X, PG, m and n are defined as above, can be prepared by alkylation of a compound of Formula (V), wherein R1, Z and X are defined as above, with a compound of Formula (VI), wherein Rx, Ry, X, PG, m and n are as defined above, as outlined in Scheme 2. The reaction can be performed in the presence of a suitable base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, in the presence of a suitable solvent such as DCM, dioxane, THF, in the presence or absence of water. The reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h. Alternatively, the Compounds of Formula (II) can be prepared by reaction of a compound of Formula (V) with an opportunely protected hydroxyalkyl carboxylic acid under Mitsunobu conditions, using conditions and methods well known to those skilled in the art such as in the presence of a phosphine, such as but not limited to triphenylphosphine, and an azadicarboxylate, such as but not limited to diisopropylazadicarboxylate.

Compounds of Formula (IV) wherein Q, Z, R1, Rx, Ry, PG, m and n are as above defined can be obtained by coupling a compound of Formula (VII) wherein Z, R1, Rx, Ry, PG, m and n are as above defined, with a compound of Formula (VIII) wherein Q is as above defined and wherein X denotes a triflate or an halide, preferably a bromide or an iodide, as outlined in Scheme 3. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling. This reaction is preferably performed with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II) or 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, Pd(Cl)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. The reaction can also be performed in the presence of a suitable copper salt such as but not limited to copper (I) iodide, copper (I) bromide or copper (I) chloride. The reaction can be performed in the presence or absence of bases such as TEA, DIEA, NMM, piperidine, Cs2CO3, sodium phosphate, in the presence or absence of a suitable solvent such as THF, ACN, DMF or acetone. This coupling reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 70° C., for a few hours, e.g. one hour to 24 h.

The method for preparing the compounds of Formula (IV) selected below:    tert-butyl{4-chloro-2-[(4-methylpyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl{4-chloro-2-[(5-cyano-2-fluorophenyl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(2-methylpyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl(4-chloro-2-{[2-fluoro-5-(hydroxymethyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-4-(hydroxymethyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-3-(hydroxymethyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-5-(methoxymethyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl{4-chloro-2-[(4-methyl-1-oxidopyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl(4-cyano-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-methyl-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-4-(methoxymethyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl{4-chloro-2-[(4-propylpyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(4-isobutylpyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl{4-cyano-2-[(4-methylpyridin-3-yl)ethynyl]phenoxy}acetate    tert-butyl{2-[(2-chlorophenyl)ethynyl]phenoxy}acetate    tert-butyl(4-chloro-2-{[5-(methylsulfonyl)-2-propylphenyl]ethynyl}phenoxy)acetate    tert-butyl[2-{[3-(propylsulfonyl)phenyl]ethynyl}-4-(trifluoromethyl)phenoxy]acetate    tert-butyl(4-cyano-2-{[5-(methylsulfonyl)-2-propylphenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[5-(methylsulfonyl)-2-piperidin-1-ylphenyl]ethynyl}phenoxy)acetate    tert-butyl(4-cyano-2-{[2-fluoro-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-chloro-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-hydroxy-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(2-{[2-chloro-5-(methylsulfonyl)phenyl]ethynyl}-4-cyanophenoxy)acetate    tert-butyl(4-cyano-2-{[5-(methylsulfonyl)-2-piperidin-1-ylphenyl]ethynyl}phenoxy)acetate    tert-butyl[(6-methyl-2-{[3-(propylsulfonyl)phenyl]ethynyl}pyridin-3-yl)oxy]acetate    tert-butyl(4-chloro-2-{[2-isopropyl-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-cyano-2-{[2-isopropyl-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(3-chloro-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({3-[(dimethylamino)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl[4-chloro-2-({5-[(diethylamino)sulfonyl]-2-methylphenyl]ethynyl)phenoxy}acetate    tert-butyl(4-chloro-2-{[2-methyl-5-(morpholiN-4-ylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({5-[(dimethylamino)sulfonyl]-2-methylphenyl]ethynyl)phenoxy}acetate    tert-butyl[4-chloro-2-({2-methyl-5-[(methylamino)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl[2-({5-[(tert-butylamino)sulfonyl]-2-methylphenyl}ethynyl)-4-chlorophenoxy]acetate    tert-butyl[4-chloro-2-({5-[(isopropylamino)sulfonyl]-2-methylphenyl]ethynyl)phenoxy}acetate    tert-butyl{4-chloro-2-[(5-{[isopropyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl(4-chloro-2-{[2-fluoro-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-cyano-2-{[2-methyl-5-(phenylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-methyl-5-(phenylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4-fluoro-2-methyl-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({3-[(methylsulfonyl)methyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl(4-fluoro-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-ethyl-5-(methylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-chloro-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-5-(isopropylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-chloro-5-(isopropylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[5-(ethylsulfonyl)-2-fluorophenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-fluoro-5-(isobutylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({2-fluoro-5-[(2-methoxyethyl)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl(4-chloro-2-{[2-methyl-5-(piperidin-1-ylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({5-[(dimethylamino)sulfonyl]-2-fluorophenyl]ethynyl)phenoxy}acetate    tert-butyl[4-chloro-2-({2-methyl-5-[(2-methylpiperidin-1-yl)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl{4-chloro-2-[(5-{[(2-methoxyethyl)(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(5-{[isobutyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl{2-[(5-{[butyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]-4-chlorophenoxy}acetate    tert-butyl[4-chloro-2-({2-methyl-5-[(4-methylpiperaziN-1-yl)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl{4-chloro-2-[(5-{[(2,2-dimethylpropyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl[2-({5-[(sec-butylamino)sulfonyl]-2-methylphenyl}ethynyl)-4-chlorophenoxy]acetate    tert-butyl{4-chloro-2-[(2-methyl-5-{[methyl(propyl)amino]sulfonyl}phenyl)ethynyl]phenoxy}acetate tert-butyl[4-chloro-2-({5-[(dipropylamino)sulfonyl]-2-methylphenyl]ethynyl)phenoxy}acetate    tert-butyl{4-chloro-2-[(5-{[(2-methoxyethyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl[4-chloro-2-({2-methyl-5-[(propylamino)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl{4-chloro-2-[(5-{[[3-(dimethylamino)propyl](methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl(2-{[5-(aminosulfonyl)-2-methylphenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl{4-chloro-2-[(5-{[cyclopentyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(5-{[[2-(dimethylamino)ethyl](methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate    tert-butyl(2-{[5-(azetidin-1-ylsulfonyl)-2-methylphenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl(4-chloro-2-{[4-(morpholiN-4-ylcarbonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({4-[(dimethylamino)carbonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl(4-chloro-2-{[3-(morpholiN-4-ylcarbonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[4-chloro-2-({3-[(dimethylamino)carbonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl[(5-chloro-3-{[3-(propylsulfonyl)phenyl]ethynyl}pyridin-2-yl)oxy]acetate    tert-butyl[(5-chloro-3-{[2-fluoro-5-(propylsulfonyl)phenyl]ethynyl}pyridin-2-yl)oxy]acetate    tert-butyl[4-chloro-2-({2-chloro-5-[(trifluoromethyl)sulfonyl]phenyl}ethynyl)phenoxy]acetate    tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-(2,4-dimethyl-1,3-thiazol-5-yl)-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[2-{[3-(propylsulfonyl)phenyl]ethynyl}-4-(2-thienyl)phenoxy]acetate    tert-butyl(4-(1-methyl-1H-pyrazol-4-yl)-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl[2-{[3-(propylsulfonyl)phenyl]ethynyl}-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy]acetate    tert-butyl[4-chloro-2-({2-methyl-5-[(methylsulfonyl)amino]phenyl}ethynyl)phenoxy]acetate    tert-butyl[4-chloro-2-({2-methyl-5-[methyl(methylsulfonyl)amino]phenyl}ethynyl)phenoxy]acetate    tert-butyl[4-chloro-2-({5-[(dimethylamino)sulfonyl]-2-methylpyridin-3-yl}ethynyl)phenoxy]acetate    tert-butyl(4-chloro-2-{[2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4′-methoxy-2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[3′-methoxy-2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4′-chloro-2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[3′-chloro-2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[2′-chloro-2-(methylsulfonyl)biphenyl-4-yl]ethynyl}phenoxy)acetate    tert-butyl[(1-{[3-(propylsulfonyl)phenyl]ethynyl}-2-naphthyl)oxy]acetate    methyl (4-chloro-2-{[2-methyl-5-(propylsulfinyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl{4-chloro-2-[(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)ethynyl]phenoxy}acetate    tert-butyl(2-{[4-(benzoylamino)phenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl(2-{[4-(acetylamino)phenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl(2-{[4-(acetylamino)-2-methyl-5-(propylsulfonyl)phenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl{4-chloro-2-[(5,5-dioxidodibenzo[b,d]thien-3-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(1,1-dioxido-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(2,2-dimethyl-1,1-dioxido-3-oxo-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(3-hydroxy-2,2-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(3-hydroxy-2,2,3-trimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(3-methoxy-2,2-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl{4-chloro-2-[(3-methoxy-2,2,3-trimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate    tert-butyl(2-{[4-{[butyl(methyl]amino)carbonyl}-3-(isopropylsulfonyl)phenyl]ethynyl}-4-chlorophenoxy)acetate    tert-butyl(4-chloro-2-{[4-[(dimethylamino)carbonyl]-3-(isopropylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4-[(diethylamino)carbonyl]-3-(isopropylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[4-{[ethyl(propyl)amino]carbonyl}-3-(isopropylsulfonyl)phenyl]ethynyl}phenoxy)acetate    tert-butyl(4-chloro-2-{[3-(isopropylsulfonyl)-4-(morpholiN-4-ylcarbonyl)phenyl]ethynyl}phenoxy)acetate    ethyl 2-(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)butanoate    ethyl 2-(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)pentanoate    ethyl 2-(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)-4-methylpentanoateis more particularly described in the examples.
Compounds of Formula (VII) wherein Z, R1, Rx, Ry, PG, X, m and n are as above defined can be obtained in a 2-step protocol as outlined in Scheme 4. The first step consists in the coupling of a compound of Formula (II) wherein Z, R1, Rx, Ry, PG, m and n are as above defined and wherein X is preferably Br, with trimethylsilylacetylene using conditions and methods well known to those skilled in the art. This reaction can be performed with or without a catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II) or 1,1-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. The reaction is preferably performed in the presence of a suitable copper salt such as but not limited to copper (I) iodide, copper (I) bromide or copper (I) chloride. The reaction can be performed in the presence or absence of bases such as TEA, DIEA, NMM, piperidine, in the presence or absence of a suitable solvent such as THF, ACN, DMF. The reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 70° C., for a few hours, e.g. one hour to 24 h. The second step consists in the removal of the trimethylsilyl protecting group, which can be accomplished by treatment with strong acids, or with potassium carbonate in methanol, or with a source of fluoride ions, such as but not limited to tetrabutylammonium fluoride or pyridinium fluoride, in the presence or absence of a suitable solvent such as THF, at a temperature between about 20° C. to about 100° C., preferably at about 70° C., for a few hours, e.g. one hour to 24 h.

Compounds of Formula (VIII) wherein Q is as above defined and X represents a halogen, preferably bromine or iodine, can be obtained as shown in Scheme 5. The first step consists in the reduction of an aryl or hetaryl nitro compound of Formula (Xa). General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling. This reaction can be performed by hydrogenolysis, with an appropriate catalyst such as but not limited to Pd/C, Pt/C, PtO2, Ni Raney, in the presence of hydrogen gas or of a source of hydrogen gas such as cyclohexadiene or ammonium formate, in a suitable solvent such as MeOH, EtOH, EtOAc, THF, DMF. This coupling reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h. The reduction can also be carried out using a metal as reducing agent, such as iron or zinc, in the presence or absence of acetic acid, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.
The second step consists in the conversion of the compounds of Formula (Xb) to the corresponding compounds of Formula (VIII), using methods well known to those skilled in the art for the conversion of an aryl or hetaryl amine to an aryl or hetaryl halide (Sandmeyer reaction and variants thereof), such as using sodium nitrite or tert-butyl nitrite and CuBr, CuI, KI or another suitable source of bromine or iodine, in a suitable solvent, such as an aqueous HCl solution, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.

Compounds of Formula (XV), wherein U is as above defined, R4 is —CH2-A wherein A is as defined above or T with p>0 and X represents an halogen or a triflate, can be obtained as shown in Scheme 6. An aromatic thiol of Formula (XI) can be alkylated with an alkyl halide of Formula (XII) in presence of a suitable base, such as but not limited to K2CO3, Cs2CO3, Na2CO3, NaOH, KOH, NaH, in a suitable solvent such as DMF, acetone, THF, in the presence of absence of water as a co-solvent, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.
The second step consists in the oxidation of the thioether group to a sulfone group, to give compounds of Formula (XIV), using oxidizing agents well known to those skilled in the art, such as but not limited to Oxone®, sodium periodate, hydrogen peroxide, 3-chloroperbenzoic acid, hydrogen peroxide in the presence of acetic acid, in a suitable solvent depending on the nature of the oxidant.
The third step consists in an aromatic bromination reaction, using a suitable source of bromine such as Br2 or NBS, in the presence of a suitable solvent such as concentrated sulphuric acid, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.

Alternatively, the compounds of Formula (XV), defined as above, can be obtained as shown in Scheme 7. Compounds of Formula (XVI) can be alkylated with a compound of Formula (XII), in presence of a suitable base, such as but not limited to K2CO3, Cs2CO3, Na2CO3, NaOH, KOH, NaH, in a suitable solvent such as DMF, acetone, THF, in the presence or absence of a water as a co-solvent, at a temperature between about 0° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.
The compounds of Formula (XV) could be obtained by oxidation, using oxidizing agents well known to those skilled in the art, such as but not limited to Oxone®, sodium periodate, hydrogen peroxide, m-chloroperbenzoic acid, hydrogen peroxide in the presence of acetic acid, in a suitable solvent depending on the nature of the oxidant.

Compounds of Formula (XXIII), wherein U and R4 are as above defined, can be prepared as shown in Scheme 8. A compound of Formula (XVIII), wherein U is as defined above, can be coupled with a compound of Formula (XIX), in the presence of a suitable base, such as K2CO3, Cs2CO3, Na2CO3, NaOH, KOH, NaH, in a suitable solvent such as DMF, acetone, THF, DMSO in the presence of absence of water as a co-solvent, at a temperature between about 20° C. to about 150° C., preferably at 20° C., for a few hours, e.g. one hour to 24 h. The compounds of Formula (XX) can be oxidized as described above, to yield the corresponding compounds of Formula (XXI).
The reduction of compounds of Formula (XXI) to afford compounds of Formula (XXII) can be performed by hydrogenolysis, with an appropriate catalyst such as but not limited to Pd/C, Pt/C, PtO2, Ni raney, in the presence of hydrogen gas or of a source of hydrogen gas such as cyclohexadiene or ammonium formiate, in the a suitable solvent such as MeOH, EtOH, EtOAc, THF, DMF. This coupling reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h. The reduction can also be carried out using a metal as reducing agent, such as iron or zinc, in the presence or absence of acetic acid, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.
The last step consists in the conversion of the compounds of Formula (XXII) to the corresponding compounds of Formula (XXIII), using methods well known to those skilled in the art for the conversion of an aryl or hetaryl amine to an aryl or hetaryl halide (Sandmeyer reaction and variants thereof), such as using sodium nitrite or tert-butyl nitrite and CuBr, CuI, KI or another suitable source of bromine or iodine, in a suitable solvent, such as an aqueous HCl solution, at a temperature between about 20° C. to about 100° C., preferably at about 20° C., for a few hours, e.g. one hour to 24 h.

Compounds of Formula (IV), wherein Q, Z, R1, Rx, Ry, PG, m and n are as defined above and R1 is Ar or Het can be obtained as described in Scheme 9. Compounds of Formula (XXIV), wherein Z, R1, Rx, Ry, PG, m and n are as defined above, and X and X′ denote suitably selected halogens or a triflate group, with X being preferentially iodine and X′ being preferentially bromine, can be coupled with compounds of Formula (III), wherein Q is as defined above.
General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling. This reaction is preferably performed with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II) or 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, Pd(Cl)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. The reaction can also be performed in the presence of a suitable copper salt such as but not limited to copper (I) iodide, copper (I) bromide or copper (I) chloride. The reaction can be performed in the presence or absence of bases such as TEA, DIEA, NMM, piperidine, Cs2CO3, sodium phosphate, in the presence or absence of a suitable solvent such as THF, ACN, DMF or acetone. This coupling reaction can be carried out at a temperature between about 20° C. to about 100° C., preferably at about 70° C., for a few hours, e.g. one hour to 24 h.
Compounds of Formula (XXV) can be coupled with aryl or heteroaryl boronic acids of Formula (XXVI), wherein R1 is Ar or Het, or the corresponding boronate esters. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling. This reaction is performed with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II), Pd(PPh3)4 or 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, Pd(Cl)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. The reaction is performed in the presence of a base such as Cs2CO3, K2CO3, CsF, in the presence of a suitable solvent such as THF, toluene or dioxane, in the presence or absence of water as a co-solvent. This coupling reaction can be carried out at a temperature between about 20° C. to about 150° C., preferably at about 120° C., for a few minutes to a few hours, possibly under microwave irradiation.

The above set out general synthetic methods may be modified to obtain compounds of Formula (I), since various suitable methods of preparation known by a person skilled in the art are available.
According to a further general process, compounds of Formula (I) can be converted to alternative compounds of Formula (I), employing suitable interconversion techniques well known by a person skilled in the art.
Suitable methods of preparation for the compounds and intermediates of the invention as known by a person skilled in the art should be used. In general, the synthesis pathways for any individual compound of Formula (I) will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
General:
The HPLC data provided in the examples described below were obtained as followed.
Condition A: Column Waters Xbridge™ C8 50 mm×4.6 mm at a flow of 2 mL/min; 8 min gradient from 0.1% TFA in H2O to 0.07% TFA in CH3CN.
Condition B: Column Waters ACQUITY UPLC® BEH C18 50 mm×2.1 mm 1.7 μm at a flow of 1 mL/min; 3 min gradient from 95% (10 mM NH4OAc in H2O)/5% CH3CN to 100% CH3CN.
Condition C: Column Waters ACQUITY UPLC® BEH C18 50 mm×2.1 mm 1.7 μm at a flow of 1 mL/min; 3 min gradient from 60% (10 mM NH4OAc in H2O)/40% CH3CN to 100% CH3CN.
Condition D: Column Waters ATLANTIS® C18 75 mm×4.6 mm, 5 μm at a flow of 0.8 mL/min; gradient from 0.1% TFA in H2O to CH3CN.
Condition E: Column Grace Vidac GENESIS® C18 50 mm×4.6 mm 5 μm at a flow of 1.0 mL/min; gradient from 0.1% HCOOH in H2O to CH3CN.
Condition F: Column Waters ATLANTIS C18 75 mm×4.6 mm, 5 μm at a flow of 1.0 mL/min; gradient from 0.1% HCOOH in H2O to CH3CN.
UV detection (maxplot) for all conditions.
The MS data provided in the examples described below were obtained as followed:
Mass spectrum: LC/MS Waters ZMD (ESI) or a Waters Acquity SQD (ESI)
The NMR data provided in the examples described below were obtained as followed: 1H-NMR: Bruker DPX-300 MHz or a Bruker DPX 400 MHz.
The microwave chemistry was performed on a single mode microwave reactor Emrys™ Optimiser from Personal Chemistry
Preparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a Sunfire Prep C18 OBD column 19×100 mm 5 μm, unless otherwise reported. All HPLC purifications were performed with a gradient of ACN/H2O or ACN/H2O/HCOOH (0.1%).
The compounds of invention have been named according to the standards used in the program “ACD/Name Batch” from Advanced Chemistry Development Inc., ACD/Labs (7.00 Release). Product version: 7.10, build: Sep. 15, 2003.